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Inhibition of forskolin‐stimulated cAMP formation in vitro by paraoxon and chlorpyrifos oxon in cortical slices from neonatal, juvenile, and adult rats
Author(s) -
Olivier Kenneth,
Liu Jing,
Pope Carey
Publication year - 2001
Publication title -
journal of biochemical and molecular toxicology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.526
H-Index - 58
eISSN - 1099-0461
pISSN - 1095-6670
DOI - 10.1002/jbt.10002
Subject(s) - muscarinic acetylcholine receptor , paraoxon , forskolin , oxotremorine , carbachol , endocrinology , medicine , chemistry , atropine , agonist , adenylyl cyclase , acetylcholinesterase , organophosphate , receptor , pharmacology , biology , biochemistry , enzyme , pesticide , agronomy
Abstract Parathion (PS) and chlorpyrifos (CPF) are organophosphorus insecticides, which elicit toxicity following biotransformation to the potent acetylcholinesterase inhibitors, paraoxon (PO) and chlorpyrifos oxon (CPO). Both oxons have also been shown to interact directly with muscarinic receptors coupled to inhibition of adenylyl cyclase. Immature animals are more sensitive than adults to the acute toxicity of PS and CPF but little is known regarding possible age‐related differences in interactions between these toxicants and muscarinic receptors. We compared the inhibition of forskolin‐stimulated cAMP formation by PO and CPO (1 nM–1 mM) in vitro in brain slices from 7‐, 21‐, and 90‐day‐old rats to the effects of well‐known muscarinic agonists, carbachol and oxotremorine (100 μM). Both agonists inhibited cAMP formation in tissues from all age groups and both were more effective in adult and juvenile (20–26% inhibition) than in neonatal (12–13% inhibition) tissues. Atropine (10 μM) completely blocked agonist‐induced inhibition in all cases. PO maximally inhibited (37–46%) cAMP formation similarly in tissues from all age groups, but atropine blocked those effects only partially and only in tissues from 7‐day‐old rats. CPO similarly inhibited cAMP formation across age groups (27–38%), but ATR was partially effective in tissues from all three age groups. Both oxons were markedly more potent in tissues from younger animals. We conclude that PO and CPO can directly inhibit cAMP formation through muscarinic receptor‐dependent and independent mechanisms and that the developing nervous system may be more sensitive to these noncholinesterase actions. © 2001 John Wiley & Sons, Inc. J Biochem Mol Toxicol 15:263–269, 2001